In recent years estrogen antagonists have become extremely important therapeutic agents for a variety of symptoms of the menopause as well as for the treatment of estrogen sensitive cancers, such as breast cancer. There are a 2 major types of estrogen antagonists.
1) the pure antiestrogens, which are typified by analogs of estradiol, substituted at C-7α-(ICI 164,384) and C-11β (RU39411). These two examples are shown in attached FIG. 1.
2) The Selective Estrogen Receptor Modulators (SERMS). These compounds have some of the structural features of the potent estrogen, diethylstilbestrol: two examples are shown in attached FIG. 2.
The SERMS are unusual antiestrogens, in that they are antiestrogenic in specific tissues, such as the uterus, breast, vagina as well as the brain, while they are estrogenic in other estrogen target organs, such as bone, liver and blood vessels. Consequently, the SERMS maintain bone density and lower blood levels of cholesterol and LDL while raising HDL. Both the pure antiestrogens and the SERMS exert their effects through the estrogen receptor, each through very different mechanisms. However, as can be seen from their structures above they share some structural features, mainly long and bulky side chains that are usually charged either with tertiary amines or carboxylic groups.
Recently the inventor has been working on the design and synthesis of locally active estrogens, “soft estrogens” that could be used for local administration to treat vaginal dyspareunia caused by the menopause or through antiestrogen therapy. These compounds were designed to be metabolically labile so that they would be destroyed rapidly in tissues and blood, thus, acting only at the site of administration, having no or little systemic action. These were structure—activity studies, in which we produced carboxylic analogs (and their esters) of different chain lengths and at different positions in the nucleus of estradiol. The theory was to produce compounds in which the carboxylic acid derivatives of estradiol are inactive while the esters are active, thus the esters are rapidly inactivated by the ubiquitous non-specific esterases. Thus, we synthesized carboxylic ester analogs at 7α-, 11β-, 15α-, and 16α-, positions in the steroid nucleus that the estrogen receptor can tolerate somewhat bulky substituents.
All of these compounds were tested in various estrogen responsive models: estrogen receptor binding by competition; estrogen potency in the Ishikawa endometrial cell; in vivo assays in rodents, local—vaginal activity, systemic—uterotrophic activity; as well as substrates for esterase activity. In general the results were unremarkable and several of the compounds have the desired properties for local therapeutic action. However, the carboxylate esters at the 11β-position gave unexpected results.